Post on 30-Mar-2019
An approach to chronic
Urticaria Dr Claudia Gray MBChB, MRCPCH, MSc, DipAllergy, DipPaedNutr
Paediatric Allergist, Red Cross Children’s Hospital and Vincent Pallotti Hospital, Cape Town
claudiagray.paediatrics@gmail.com
Introduction
Chronic urticaria ± angioedema are not
life threatening, but
Cause misery, embarrassment, discomfort
↓ QoL comparable to triple coronary
heart disease
O`Donnell B et al, the impact of chronic urticaria on quality of life.
Br J Dermatol. 1997; 136: 553-6
Introduction
There is no cure
Adequate treatment should enable patient
to lead an essentially normal life
Patients are entitled to expect effective
treatment to achieve this goal, which in
selected cases may involve potent and
expensive medications
Introduction: definitions
Chronic urticaria (CU) is a condition in
which wheals, with or without
concomitant angioedema, occur daily or
near daily for ≥ 6 weeks
Includes episodic acute intermittent
urticaria/angioedema lasting hours-days
and recurring over months or years
Prevalence approx 1% of population
Introduction: definitions
Acute urticaria (CU) is a single episode of
urticarial illness lasting < 6 weeks
Prevalence approx 15% of population
Usually self-limiting
Cause more likely to be found
Introduction: definitions
Angioedema without urticaria requires a
different approach
Rule out hereditary angioedema (HAE)-
which behaves differently to CU and can
be life threatening
What is Urticaria?
Hives/wheals/weals/welts/”bommels”
Red raised itchy rash or pale with
surrounding flare
Superficial skin layers
Mast cell activation →release of histamine
and other inflammatory mediators→
Increased blood flow and vascular
permeability in superficial skin layers
What is Urticaria?
Lesions single or numerous
Few mm to hand-sized
Arise spontaneously, peak between 8-12
hours, resolve by 24 hours.
Extremely itchy; characteristically relieved
by rubbing as opposed to scratching
What is Angioedema?
Tissue swelling as a result of ↑ vascular
permeability in the deeper layer of the
skin (dermal/subcutaneous)
Most evident in the oropharynx, around
eyes, abdomen and genitalia
Involves mucous membranes, unlike
urticaria
What is Angioedema?
Angioedema is painful rather than itchy
Can persist for several days
Life threatening airway compromise has
not been described with chronic urticaria
with angioedema (unlike HAE)
Co-existence of Urticaria and
Angioedema?
Urticaria alone in 20-50% cases CU
Urticaria + angioedema in 40-80%
Angioedema alone in 10%
Mechanisms
Trigger
↑ mast cell releasibility
• Immediate release of histamine
• Subsequent release of membrane derived mediators (leukotrienes, PG)
• Other non-histamine mechanisms eg C5a
• Perpetuation of inflammatory response by cellular infiltrate
Mechanisms
Release of mediators is confined to the
skin and submucosa, thus the
cardiorespiratory compromise of
anaphylaxis does not occur
Mechanisms
What causes mast cell activation?
In many cases unknown (idiopathic)
In some cases IgE receptor is chronically
stimulated by IgG antibodies
(autoimmune)
Other triggers
Aetiology
What causes persistent/recurrent mast cell activation in CU?
Causative versus aggravating factors
FACT: majority of patients with CU are referred to allergy clinics to determine what food/preservative they are allergic to
REALITY: majority are “idiopathic” and hopelessly over-investigated
Aetiology
FACT: majority of patients with CU are
referred to allergy clinics to determine
what food/preservative they are allergic
to
REALITY: majority are “idiopathic” and
hopelessly over-investigated
Aetiological Classification of CU AETIOLOGY COMMENTS
IDIOPATHIC 40-50% of cases
AUTOIMMUNE Autoantibodies to IgE/IgE receptor: 30-
50%
PHYSICAL STIMULI Cold, aquagenic, cholinergic,pressure
DRUG INDUCED ACEI, NSAIDS
ALLERGIC CONTACT Contact urticaria to latex/food/grass
NON-IgE MEDIATED MAST CELL
DEGRANULATION
E.g. opiates
CI INHIBITOR DEFICIENCY Angioedema without urticaria
FOOD CONSTITUENT Rare! But often perceived as the cause
LYMPHOPROLIFERATIVE DISORDERS
VASCULITIS Painful urticaria
CRYOPYRIN ASSOCIATED PERIODIC
SYNDROME; SCHNITZLER’S
SYNDROME
Extremely rare, cold associated
systemic symptoms
1. Chronic Idiopathic Urticaria
Majority of CU cases
No consistent relationship with
aetiological agent
Triggering stimulus is elusive
Unpredictable mast cell granulation
Investigations typically negative, and
should be minimal
Chronic Idiopathic Urticaria
May be aggravated by:
1. Viral infections:
◦ Worsened for up to 6 weeks afterwards
2. Stress
◦ Possibly via ↑ release of corticotrophin-releasing hormone (CRH) in the skin
◦ Attach to CRH-receptor on mast cells which trigger degranulation
2. Autoimmune Chronic Urticaria
Subgroup of CIU which test positive to
autoantibodies:
◦ Most commonly IgG antibody to α-subunit of
IgE receptor on mast cells
◦ Rarely IgG to IgE which is bound to mast cells
30-50% of adults and children with
chronic urticaria
Mast cells chronically stimulated
Autoimmune Chronic Urticaria
Pathogenesis also involves activation of classical
complement pathway and stimulation of
complement C5a
Explains why autoimmune activation is confined
to the skin as the lung does not have C5a
receptors
Autoimmune Chronic Urticaria
30-50% of adults and children with CU have
positive autoimmune tests
Associated in 30% of adults with antithyroid
antibodies, indicating a general autoimmune
tendency
Autoimmune Chronic Urticaria
Diagnostic tests:
1. Autologous serum skin test
◦ 0.1 mL of patient’s serum is injected into patients forearm intradermally, with a saline control. Watch for swelling and flare after 25-30 minutes
◦ 70-80% sensitive and specific
2. Measurement of levels of the anti-IgE
antibodies
◦ Only in specialised overseas laboratories
Autoimmune Chronic Urticaria
Importance of making a diagnosis:
Importance of making a diagnosis
Provides an explanation
Makes further investigations unnecessary
Prognostication: usually a more
intense, difficult to treat and
protracted course
3. Food Triggers
Very very rarely the cause
Patients frequently analyse foods/additives
they have eaten that day in search of a
connection with symptoms
Food Triggers
Genuine IgE mediated Food
Allergy
“Food reaction” in CU
Occur within 2 hours of ingestion CU rash often starts in the night or
early morning hence > 6 hours after
eating
Symptoms are reproducible after
each exposure
Symptoms not reproducible with
each exposure
Short lived wheals < 6 hours Wheals come and go over several
days
Part of a complex of symptoms eg
flushing, pruritis, gastrointestinal,
chest or cardiovascular symptoms
Only wheals ± angioedema
Food Triggers
Preservatives/Additives?
Not the cause; may be a trigger/ aggravator
Cohort at RXH, 10% of CU sufferers were
sensitised to preservatives (NB benzoates,
tartrazine); elimination caused some ↓
frequency of symptoms but did not “take it
away”
CAST tests to preservatives are available
Salicylates may trigger CU by a non-IgE
mediated mechanism
Food Triggers
Patients with CU may report worsening with
rich fermented/spicy food or alcohol
Probably related to histamine content and
vasodilatory properties of these foods rather
than an allergy
Allergic Contact Urticaria
Local urticaria after contact with allergens via
an IgE-mediated mechanism
Eg latex, egg, dog saliva, grass
Diagnosed by SPT and specific IgE levels
Infections
Association of CU with parasites, EBV,
Hep B, viral infections, fungal infections
Very rarely causative
Diagnostic testing directed by clinical
history
Mechanism: immune complex formation
with antibody and antigen, leading to c5a
activation which binds to mast cell
receptors
Infections
Helicobacter Pylori
◦ was in vogue as potential cause of CU a few
years ago
◦ results not reproducible
◦ high background of asymptomatic H pylori
infection makes interpretation difficult
Physical Urticarias
Urticaria induced reproducibly by a physical stimulus
Physical trigger causes direct mast cell activator release
Symptoms usually of quick onset and short duration
Often resistant to standard therapy
Can occur in conjunction with CIU/Autoimmune urticaria
Diagnosed by challenge tests to appropriate stimuli
Physical Urticarias
Exercise
Solar urticaria
Aquagenic urticaria
Vibratory (use of vibratory building tools)
Drug Induced Urticaria
NSAIDS
Aspirin
Antidepressants (citalopram)
Statins
Anti-epileptics
Opiates
Generally via a non-IgE mediated mechanism
Urticarial Vasculitis
Small vessel vasculitis due to deposition of immunoglobulins and complement
Assoc with infections, autoimmune disorders, malignancy
Symptoms such as fever, weight loss, lymphadenopathy
Lesions last > 24 hours
Leave bruising
Painful rather than itchy
Skin biopsy usually needed for diagnosis
Angioedema without Wheals
ACEI-related angioedema 0.1-0.2%
Can occur several weeks or months after
starting the medication
Involves ↑ bradykinin
Can involve larynx, hence all ACEI treatment
should be withdrawn
Swelling may take weeks to months to settle
Angiotensin receptor blocking drugs can
usually be used
Angioedema without Wheals
2. C1esterase inhibitor deficiency
Hereditary
angioedema type 1
• Hereditary
• Low levels of C4 and C1inhibitor levels
Hereditary angioedema type 2
• hereditary
• Normal levels but poor functioning C1 inhibitor
Acquired
• C1inhibitor deficiency caused associated with malignancies e.g. paraproteinaemias
Diagnosis of Chronic Urticaria
1. Clinical History
KEY!
Nature of lesions?
Duration?
Residual bruising?
Angioedema?
Other symptoms?
Family history angioedema/ unexplained abdo pain/unexplained airways obstruction etc
Drug History
Diagnosis of Chronic Urticaria
2. Special Investigations
Basic screen:
1. FBC
2. ESR
3. Urine dipstick
4. TFT and autoantibodies
Diagnosis of Chronic Urticaria
2. Special Investigations
Basic screen:
1. FBC
(eosinophilia/anaemia/neutrophilia)
2. ESR
(chronic infection/vasculitis/paraproteinaemia)
3. Urine dipstick
(UTI, vasculitis)
4. TFT and autoantibodies
Diagnosis of Chronic Urticaria
2. Special Investigations
Further investigations as guided by history
Symptom diary may be useful before
embarking on extensive and expensive
testing
Further Investigations
A. Directed allergy testing
Skin Prick Tests useful of any suspicion of
allergen triggers
◦ Visual and at point of care
◦ Usually disproves the suspicion
CAST tests for preservatives only if a high
suspicion
Further Investigations
B. For suspected vasculitis/connective
tissue disease
ANA, anti- DS DNA
Biopsy of suspected vasculitis lesions
Further Investigations
C. Provocation (challenge) testing
◦ Ice cube test
◦ Submersion of a limb in water (hot/cold)
◦ Exercise
Further Investigations
E. Hereditary angioedema screening
◦ In isolated angioedema
◦ C4 levels (low in HAE)
◦ C1 esterase inhibitor levels
◦ C1 esterase function tests
Differentials
Urticarial Vasculitis
Cryoglobinaemia
Cryopyrin associated periodic syndromes
Polymorphic eruption of pregnancy
Mastocytosis (condition with
overproliferation and accumulation of
tissue mast cells)
Recurrent erythema multiforme
Treatment of Chronic Urticaria
1. Avoidance of Triggers
2. Control symptoms with second/third generation antihistamines (upward titration)
3. Consider other treatment options: ◦ Sedating antihistamines at night
◦ LTRA
◦ Tranexamic acid for angioedema
◦ Immune modulators
◦ (Anti-IgE)
1. Avoidance of triggers
Treat underlying infection/malignancy
Avoid triggering allergens: NO BLANKET
ELIMINATION DIETS
Trial off possibly causative medications for
several months
2. Second/third generation
antihistamines Mainstay of treatment
Active against H1 receptor
Better tolerated and fewer CNS side effects than 1st generation antihistamines
Individual patients responses and side effects vary-
May cause mild sedation hence patients should be advised to and excess alcohol and that performance of complex tasks may be affected- but generally very well tolerated
2. Second/third generation
antihistamines: how to dose? Start with recommended daily dose for a
few days to make sure that tolerated
Incrementally increase the dose according to response up to 4X recommended dose
Once treatment control established, continue treating 3-12 months (or longer) then gradual withdrawal
For patient with infrequent symptoms, may be taken as required or prophylactically before special occasions
2. Second/third generation
antihistamines: which drug?
Loratadine
Cetirizine
Fexofenadine all licensed for CU
Desloratadine
Levocetirizine
2. Second/third generation
antihistamines: which drug? Very few comparator trials-
Cetirizine seems to have the slight upper hand
Handa S, Dogra S, Kumar B. Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria. J Dermatolog Treat 2004; 15:55–7.
Combination of 2 non-sedating antihistamines may be tried if a single type inadequate, or a trial of a different non-sedating antihistamine
3. First generation anti-histamines
Highly sedating and many side effects
May be useful for short term addition to
newer antihistamines to gain symptom
control
Not ideal long term
Hydroxyzine
Chlorphenamine
Promethazine
Sedating antihistamines ctd
Doxepin
Doxepin is a tricyclic antidepressant which is useful in the treatment of antihistamine -resistant urticaria
•Dose range is 25-75mg daily
•High affinity for H1 receptor (8x greater than diphenhydramine)
•Significant H2 blocking activity
•Cautions : 1.Never withdraw abruptly
2.Do not administer concurrently with other anti-depressants
3.Do not administer to patients with significant heart disease
4.Possesses significant anti-muscarinic activity
Other treatment options
Anti-histamines may not be entirely
effective in controlling CU
Variety of other cytokines which are not
blocked by antihistamines may be
involved:
◦ Leukotrienes
◦ Prostaglandin D2
◦ Kinins
Other treatment options
1. Leukotriene receptor antagonists
◦ Useful in combination with antihistamines in a
subgroup of patients
◦ Safe drug with rapid onset of action therefore
worth a trial
◦ Particularly useful in those with
- chronic autoimmune urticaria
- adverse response to NSAIDs/aspirin
- delayed pressure urticaria
Other treatment options
2. H2 receptor antagonists
◦ Target histamine binding to the H2 receptor
◦ May provide marginal benefit in combination
with H1 receptor blockers
◦ E.g ranitidine
◦ Sharpe and Shuster. In dermographicurticariaH2 receptor
antagonists have a small but therapeutically irrelevant effect
compared with H1 antagonists alone. BJD 2006; 129: 575-9
Other treatment options
3. Corticosteroids
◦ Short course of oral steroids can be added to
antihistamines in severe cases or if rapid relief
required
◦ Long term low dose corticosteroids may be
needed in stubborn cases
◦ Useful for urticarial vasculitis
◦ Significant systemic side effects
Other treatment options
4. Immune modulators
◦ For severe unremitting disease uncontrolled
by antihistamines
◦ Most experience is with ciclosporin
◦ Grattan et al, BJD 2000; 143: 365-72; Vena et al, JAAD 2006; 5:
705-09; Inalozet al, J Dermatol. 2008; 35: 276-82
Other treatment options
4. Ciclosporin
◦ Can have rapid onset of action
◦ Monitor BP and renal function
◦ Treatment usually maintained for 3-6 months then slowly withdrawn
◦ After ciclosporin withdrawal:
-1/3 excellent long term response
-1/3 mild relapse and can be maintained on
anti-histamine;
-1/3 relapse and need to resume cyclosporin
treatment
Other treatment options
5. Tranexamic acid
◦ For severe angioedema
◦ Inhibits conversion of plasminogen→plasmin
(plasmin→bradykinin)
◦ Also useful in prophylaxis for HAE cases
Other treatment options
6. Anti-IgE antibody (omalizumab)
◦ Humanised anti IgE antibody, subcut injection
◦ Early trials and case reports very promising
◦ Rapid reduction in symptoms, then long term
(6 month) relief after only one dose
◦ Kaplan et al. JACI 2008; 122: 569-73
◦ Goberet al JACI 2008; 121 S147
Other treatment options
7. IV immunoglobulin
◦ 400 mg/kg for 5 days was shown to have good
benefit in 9/10 patients with severe
autoimmune CU.
◦ 3/10 had long term benefit
◦ O`Donnell et al BJD 1998; 138: 101-6)
Other treatment options
8. Adrenaline
◦ Never for isolated urticaria
◦ Only if severe angioedema affecting the upper
airway
Other Treatment Options
9. Experimental treatment options:
◦ Nifedipine
◦ Colchicine
◦ Sulphasalazine
◦ Dapsone
◦ Methotrexate
Treatment algortithm
Standard dose non sedating H1 antihistamine
Higher dose (up to 4x) non sedating H1 anti histamine or add a second non-sedating anti-histamine
Consider adding a sedating anti-histamine at night short term
Add second line agent eg LTRA, ranitidine and tranexamic acid (if predominantly angioedema)
Add or substitue ciclosporin, low dose Corticosteroid or anti IgE
Prognosis
Duration of illness 2-10 years
25% have remission within the first 3
years
20% of adults with CU still have
symptoms after 10 years
Severity of illness, presence of
angioedema, positive antithyroid
antibodies, and positive ASST
↑ severity and persistence
Overall summary
Chronic urticaria can be demoralising and
disfiguring for the patient
Up to 90% of cases of chronic urticaria
are idiopathic or autoimmune
Most cases are overinvestigated
Food allergy is extremely rarely a trigger
Spicy foods/ certain preservatives may
trigger exacerbation but are not the
primary cause
Overall summary
An excellent history is the mainstay of
diagnosis
A basic batch of screening tests is
recommended (FBC, ESR, TFT, Urine dip)
Further tests are guided by the history
and include allergen testing, provocation
tests
Don`t waste time on unproven and
ineffective treatments and “allergy tests”
Overall summary
Treatment is based on avoiding triggers and giving newer generation antihistamines at up to 2-4 x the recommended dose.
Other treatment options including LTRA, ranitidine and ciclosporin are available and are added to antihistamines in resistant cases.
Anti-IgE antibody holds much promise but is not yet available in SA
When all else fails- revisit the diagnosis